[NTR] follicular CD8-positive, alpha-beta T cell #3674

New term request: follicular CD8-positive, alpha-beta T cell

Proposed label: follicular CD8-positive, alpha-beta T cell

Definition: A CD8-positive, alpha-beta T cell that expresses the follicle-homing chemokine receptor CXCR5 (C-X-C chemokine receptor type 5) and lacks CCR7, enabling entry into the CXCL13-rich B-cell follicle and germinal center of secondary lymphoid organs (PMID:11104798; PMID:29085360). First characterised in human tonsil follicles, this subset localises to germinal centers where it combines cytolytic effector capacity — marked by perforin and granzyme B expression — with the ability to suppress T follicular helper-driven B cell differentiation into plasmablasts (PMID:31028278; PMID:28100833). It is also referred to as the follicular cytotoxic CD8 T cell (Tfc) or CXCR5+CD8+ T cell. This is a general follicular population of secondary lymphoid organs — documented in human and murine lymph node and spleen as well as tonsil (PMID:29085360) — and is not tonsil-restricted.

Parent (is_a): CD8-positive, alpha-beta T cell (CL:0000625)

Anatomical location: germinal center (UBERON:0010754)

Logical axioms:

• part of (BFO:0000050) some germinal center (UBERON:0010754) — Resides within the germinal center of secondary lymphoid organs (broad ASTA search: not tonsil-restricted); the source atlas sampled human palatine tonsil.
• has plasma membrane part (RO:0002104) some C-X-C chemokine receptor type 5 (PR:000001209) — CXCR5 surface protein expression is the hallmark defining marker, confirmed by flow cytometry and immunostaining in human tonsil studies (PMID:11104798; PMID:29085360). This axiom distinguishes this cell from all other CD8+ alpha-beta T cell subtypes under the parent.
• has plasma membrane part (RO:0002104) some T-cell surface glycoprotein CD8 alpha chain (PR:000001084) — CD8 alpha chain surface expression defines the CD8+ coreceptor lineage, confirmed by flow cytometry (PMID:29085360; PMID:31028278). Already implied by parent CL:0000625 but included for completeness in the equivalence pattern.
• capable of (RO:0002215) some T cell mediated cytotoxicity (GO:0001913) — Follicular CD8 T cells retain cytolytic capacity (perforin, granzyme B) and can kill target cells; demonstrated in vitro via bispecific antibodies and inferred from high ex vivo granzyme B / perforin expression (PMID:28100833; PMID:37205767).
• capable of (RO:0002215) some negative regulation of B cell differentiation (GO:0045578) — CXCR5+CD8+ T cells suppress Tfh-mediated differentiation of naive and memory B cells into plasmablasts, a defining regulatory function of this subset (PMID:31028278; PMID:30344522).

Synonyms:

• CXCR5-positive CD8-positive, alpha-beta T cell (exact)
• follicular cytotoxic CD8 T cell (exact)
• Tfc cell (related)
• fCD8 T cell (related)
• germinal center CD8 T cell (related)

References:

• Schaerli et al. (2000). DOI: 10.1084/jem.192.11.1553 ; PMID:11104798 — First characterisation of CXCR5+ T cells in human tonsil follicles; establishes CXCL13-driven homing as the mechanism of follicular entry
• Perdomo-Celis et al. (2017). DOI: 10.3389/fimmu.2017.01241 ; PMID:29085360 — Defines follicular CD8 T cell phenotype (CXCR5+, CCR7-), mechanism of follicular entry, and CXCL13 migration; reviews origin and function during HIV infection
• Petrovas et al. (2017). DOI: 10.1126/scitranslmed.aag2285 ; PMID:28100833 — Characterises follicular CD8 T cells (fCD8/Tfc) in human lymph nodes and tonsils; demonstrates cytolytic potential (granzyme B, perforin) and germinal-center accumulation
• Chu et al. (2019). DOI: 10.1038/s41375-019-0464-2 ; PMID:31028278 — Transcriptional distinctiveness (77 DEGs), antitumor function, and suppression of Tfh-mediated B cell differentiation into plasmablasts; confirms CXCR5+CD8+ subset identity
• Shen et al. (2018). DOI: 10.3389/fimmu.2018.02287 ; PMID:30344522 — Germinal-center localisation in human tonsils and lymph nodes; helper function for B cell immunoglobulin production
• Collins et al. (2023). DOI: 10.1126/sciimmunol.ade5872 ; PMID:37205767 — Cytolytic surveillance of germinal centers; perforin and granzyme B expression in HIV controllers; fCD8 terminology
• King et al. (2021). DOI: 10.1126/sciimmunol.abh3768 ; PMID:34623901 — Atlas paper (Azimuth human_tonsil_v2) in which the follicular CD8 T cell annotation is embedded

Justification: No CL term exists for a follicular or CXCR5-positive CD8 T cell. Exhaustive OLS4 searches for 'follicular CD8 T cell', 'follicular cytotoxic T cell', 'CXCR5-positive CD8 T cell', and 'cytotoxic T lymphocyte follicular' returned zero results. The search for 'follicular T cell' returned only CD4-lineage terms: CL:0002038 (T follicular helper cell, CD4-positive) and CL:0009062 (germinal center T cell, also CD4-positive). Among existing CD8 alpha-beta subtypes (central memory, effector memory, naive, cytotoxic, regulatory, resident memory), none captures the CXCR5+ follicular/germinal-center specialisation that defines this population. The nearest existing term, CL:0000625 (CD8-positive, alpha-beta T cell), is a valid broad parent but lacks the follicular localisation, CXCR5 surface expression, CCR7 negativity, and dual cytolytic-regulatory function that distinguish this subset.

CORRECTION OF PRIOR AZIMUTH MAPPING: The published Azimuth human_tonsil_v2 curated CL map assigned CL:0000895 (naive thymus-derived CD4-positive, alpha-beta T cell) to this cell type. This is biologically incorrect on every key axis: CL:0000895 is CD4-positive, CCR7-positive, naive, and T-cell-zone resident, whereas the follicular CD8 T cell is CD8-positive, CCR7-negative, antigen-experienced (memory/effector), and germinal-center resident. The correct parent is CL:0000625 (CD8-positive, alpha-beta T cell). CL editors should be aware that CL:0000895 was the Azimuth assignment and should not be retained.

Proposed logical axioms (human-readable):

• subClassOf 'part of' some palatine tonsil (UBERON:0002373) — cell resides in the B-cell follicle/germinal center of the palatine tonsil
• subClassOf 'has plasma membrane part' some C-X-C chemokine receptor type 5 (PR:000001209) — defining surface marker; confirmed by flow cytometry and immunostaining in human tonsil (PMID:11104798; PMID:29085360)
• subClassOf 'has plasma membrane part' some T-cell surface glycoprotein CD8 alpha chain (PR:000001084) — CD8 coreceptor surface expression; confirmed by flow cytometry
• subClassOf 'capable of' some T cell mediated cytotoxicity (GO:0001913) — cytolytic capacity demonstrated by perforin/granzyme B expression and in vitro killing (PMID:28100833; PMID:37205767)
• subClassOf 'capable of' some negative regulation of B cell differentiation (GO:0045578) — suppression of Tfh-mediated plasmablast differentiation (PMID:31028278; PMID:30344522)

Note on CCR7: CCR7 is characteristically absent (CCR7-negative), which releases the cell from T-cell zone retention and is complementary to CXCR5-driven follicular homing. CCR7 negativity is documented textually and should not be encoded as a positive membrane axiom. [Revised 2026-07-28: de-anchored from palatine tonsil. A broad ASTA tissue-distribution search established this is a general population of secondary lymphoid organs / MALT rather than a palatine-tonsil-specific type; the tonsil is merely the tissue sampled by the atlas. Label and location axiom generalised accordingly (location → germinal center, UBERON:0010754).

Source: Azimuth human_tonsil_v2 fine label; atlas Massoni-Badosa et al. 2024 (An atlas of cells in the human tonsil, Immunity, DOI 10.1016/j.immuni.2024.01.006); King et al. 2021 upstream starting annotation. Draft for review — not yet submitted.